Fluoroalkyl-substituted isochromanone compound as well as preparation method and application thereof

Abstract

The invention discloses a preparation method of a fluoroalkyl-substituted isochromanone compound in the technical field of organic synthesis, and the preparation method specifically comprises the following steps: mixing 2-allyl aromatic formic acid, difluoro or perfluoroalkyl iodide, silver salt and an organic solvent, and carrying out heating reaction and subsequent separation and purification to obtain the fluoroalkyl-substituted isochromanone compound. According to the method, the starting raw materials are cheap and easy to obtain, the operation is simple, the use of a high-dose redox reagent and an additional reaction additive is avoided, a simple and efficient preparation method is provided for the fluoroalkyl-substituted isochromanone compound, and meanwhile, the fluorine-containing isochromanone compound provided by the invention has certain activity of resisting leukemia cell growth and has a good application prospect. The compound can be applied to preparation of anti-leukemia drugs. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a fluoroalkyl-substituted isochromanone compound, a preparation method and application thereof. Background Art

[0002] Isochromanone is an important class of heterocyclic molecules that can be widely used in the fields of medicinal chemistry and synthetic chemistry as active molecules or organic synthesis intermediates. For example, dihydroisocoumarin containing an isochromanone skeleton has anticancer activity (BioconJugChem.2009,20,1737). Therefore, developing new experimental methods to achieve efficient synthesis of new isochromanone molecules is of great significance for expanding the sources of important isochromanone skeleton compounds in medicinal chemistry and the discovery of lead compounds. Due to the high electronegativity of fluorine, fluoroalkyl modification strategies are widely used in the design of pharmaceutically active molecules, aiming to improve the lipophilicity, metabolic stability and pharmacological activity of the parent molecule. Therefore, the development of synthetic methods for difluoroalkyl and polyfluoroalkyl modified isochromanone compounds has an important role in promoting the further development of the medicinal activity value of related molecules.

[0003] However, although there are many strategies for the formation of lactones through cyclization reactions involving fluoroalkyl groups, they often require the use of palladium (J. Fluo. Chem. 2005, 126, 319) and metal iridium catalysts (J. Org. Chem. 2017, 82, 9824), and the prior art does not involve the synthesis of isochromanone compounds. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention designs a silver-catalyzed tandem cyclization reaction to synthesize fluoroalkyl-substituted isochromanone compounds.

[0005] One of the purposes of the present invention is to provide a fluoroalkyl-substituted isochromanone compound, characterized in that its structural formula is as follows:

[0006]

[0007] wherein R is independently selected from hydrogen, 8-fluoro, 8-chloro, 8-bromo, 8-iodo, 7-fluoro, 7-chloro, 7-bromo, 7-iodo, 7-trifluoromethyl, 7-methoxy, 7-methyl, 6-fluoro, 6-chloro, 6-bromo, 6-iodo, 6-trifluoromethyl, 6-methoxy, 6-methyl, 5-fluoro, 5-chloro, 5-bromo, 5-iodo, 5-methyl, 5-trifluoromethyl, 5-methoxy, 6, 7-dimethoxy, 6, 7-dimethyl, 6 -fluoro-7-methoxy, 6-bromo-7-methoxy, 6-chloro-7-methoxy, 6-iodo-7-methoxy, 6-methoxy-7-iodine, 6-methoxy-7-bromo, 6-methoxy-7-chloro, 6-methoxy-7-fluoro, 7-bromo-8-fluoro, 6-bromo-7-fluoro, 6,7-difluoro, 6,7-dichloro, 5-methoxy-8-fluoro, 5-methoxy-8-chloro, 5-methyl-8-fluoro or 5-methyl-8-chloro;

[0008] R' is selected from ethoxycarbonyl, methoxycarbonyl, perfluoro-n-butyl, perfluoro-n-propyl, perfluoro-isopropyl, perfluoro-n-pentyl, perfluoro-n-hexyl, perfluoro-n-heptyl or perfluoro-n-octyl.

[0009] The second object of the present invention is to provide a method for preparing a fluoroalkyl substituted isochromanone compound, which comprises: mixing 2-allylcarboxylic acid, difluoro or perfluoro iodoalkane, silver salt and an organic solvent, heating the mixture for reaction and subsequent separation and purification to obtain a fluoroalkyl substituted isochromanone compound;

[0010]

[0011] Further, the silver salt is selected from silver acetate, silver oxide, silver carbonate, silver trifluoroacetate or silver chloride, preferably silver oxide.

[0012] Furthermore, the organic solvent is selected from acetonitrile, tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or ethyl acetate, preferably 1,4-dioxane.

[0013] Furthermore, the temperature is 20°C to 100°C, preferably 50°C to 80°C; more preferably 70°C; the time is 2h to 40h, preferably 12h to 48h; preferably 36h; the gas atmosphere is selected from air, nitrogen or argon, most preferably argon.

[0014] Further, the molar ratio of 2-allylcarboxylic acid: difluoro or perfluoro iodoalkane: silver salt is 1:1 to 5:0.1 to 2. Preferably, the molar ratio of 2-allylcarboxylic acid: difluoro or perfluoro iodoalkane: silver salt is 1:3:0.5.

[0015] Furthermore, the separation and purification method is selected from silica gel column chromatography and recrystallization; preferably silica gel column chromatography separation.

[0016] The third object of the present invention is to provide the use of fluoroalkyl substituted isochromanone compounds in the preparation of anti-leukemia drugs.

[0017] In view of the fact that silver salts are often used as good bases, transition metals and single-electron oxidants, the present invention innovatively develops a silver-catalyzed tandem cyclization reaction to synthesize fluoroalkyl-substituted isochromanone compounds. The starting materials of this method are cheap and readily available, the operation is simple, and the use of high doses of redox reagents and additional reaction additives is avoided, providing a simple and efficient preparation method for fluoroalkyl-substituted isochromanone compounds.

[0018] Experiments have confirmed that the fluoroalkyl-substituted isochromanone compounds described in the present application have certain anti-leukemia (human myeloid leukemia cell HL-60) drug activity. Therefore, the present application also provides the use of fluoroalkyl-modified isochromanone compounds in drugs for treating leukemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Compound 2a prepared in Example 1 1 H NMR spectrum;

[0020] Figure 2 Compound 2a prepared in Example 1 13 C NMR spectrum;

[0021] Figure 3 Compound 2a prepared in Example 1 19 F NMR spectrum;

[0022] Figure 4 Compound 2b prepared in Example 2 1 H NMR spectrum;

[0023] Figure 5 Compound 2b prepared in Example 2 13 C NMR spectrum;

[0024] Figure 6 Compound 2b prepared in Example 2 19 F NMR spectrum;

[0025] Figure 7 Compound 2c prepared in Example 3 1 H NMR spectrum;

[0026] Figure 8 Compound 2c prepared in Example 3 13 C NMR spectrum;

[0027] Fig. 9 Compound 2c prepared in Example 3 19F NMR spectrum;

[0028] Fig.10 Compound 2d prepared in Example 4 1 H NMR spectrum;

[0029] Fig.11 Compound 2d prepared in Example 4 13 C NMR spectrum;

[0030] Fig.12 Compound 2d prepared in Example 4 19 F NMR spectrum;

[0031] Fig.13 The compound 2e prepared in Example 5 1 H NMR spectrum;

[0032] Fig.14 The compound 2e prepared in Example 5 13 C NMR spectrum;

[0033] Fig.15 The compound 2e prepared in Example 5 19 F NMR spectrum;

[0034] Fig.16 Compound 2f prepared in Example 6 1 H NMR spectrum;

[0035] Fig.17 Compound 2f prepared in Example 6 13 C NMR spectrum;

[0036] Fig.18 Compound 2f prepared in Example 6 19 F NMR spectrum;

[0037] Fig.19 2g of the compound prepared in Example 7 1 H NMR spectrum;

[0038] Fig. 20 2g of the compound prepared in Example 7 13 C NMR spectrum;

[0039] Fig.21 2g of the compound prepared in Example 7 19 F NMR spectrum;

[0040] Fig. 22 Compound 2k prepared in Example 11 1 H NMR spectrum;

[0041] Fig.23 Compound 2k prepared in Example 11 13 C NMR spectrum;

[0042] Fig.24 Compound 2k prepared in Example 11 19 F NMR spectrum;

[0043] Fig.25 Compound 21 prepared in Example 12 1 H NMR spectrum;

[0044] Fig.26 Compound 21 prepared in Example 12 13 C NMR spectrum;

[0045] Fig. 27 Compound 21 prepared in Example 12 19 F NMR spectrum;

[0046] Fig.28 Compound 2m prepared in Example 13 1 H NMR spectrum;

[0047] Fig.29 Compound 2m prepared in Example 13 13 C NMR spectrum;

[0048] Fig.30 Compound 2m prepared in Example 13 19 F NMR spectrum;

[0049] Fig.31 Compound 3 prepared in Example 14 1 H NMR spectrum;

[0050] Fig.32 Compound 3 prepared in Example 14 13 C NMR spectrum;

[0051] Fig.33 Compound 3 prepared in Example 14 19 F NMR spectrum. DETAILED DESCRIPTION

[0052] The following is further described in detail through specific implementation methods:

[0053] Example 1

[0054] Taking the preparation of the isochromanone compound 2a with the following structural formula as an example, the raw materials and preparation method used are:

[0055] 2-allyl-4-bromobenzoic acid (0.2 mmol), Ag 2 O (0.1mmol), 1,4-Dioxane (2mL), added to a 10mL reaction bottle, followed by ethyl difluoroiodoacetate (0.6mmol). After the reaction bottle was evacuated with an oil pump, argon was injected into the bottle (repeated three times), and it was placed in a 70°C oil bath and stirred for reaction. After 36 hours, the reaction was cooled to room temperature. The reaction solution was extracted, dried, filtered, concentrated and chromatographed on a silica gel column to obtain a light yellow oily liquid compound 2a (53.2mg, 73% yield).

[0056] The test data of product 1a are as follows:

[0057] 1 H NMR (400 MHz, CDCl 3 )δ7.92(d,J=8.3Hz,1H),7.54(d,J=8.3Hz,1H),7.44(s,1H),4.89–4.80(m,1H),4.39(q,J=7. 2Hz,2H),3.06(d,J=10.8Hz,2H),2.86–2.70(m,1H),2.54–2.41(m,1H),1.38(t,J=7.2Hz,3H).

[0058] 13 C NMR (101 MHz, CDCl 3 )δ163.5,163.4,139.8,132.0,131.6,130.7,129.2,123.6,114.3(t,J=246.5Hz),72.5,63.6,39.8(t,J=23.8Hz),32.9,14.0.

[0059] 19 F NMR (376 MHz, CDCl 3 )δ-101.35–-102.26(m,1F),-106.64–-107.79(m,1F).

[0060] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 14 H 14 F 2 O 4 ,363.0038;Found:363.0033.

[0061] Example 2

[0062] Prepare isochromanone compound 2b with the following structural formula:

[0063] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allyl-5-bromobenzoic acid, and the other conditions were the same as in Example 1, and finally a light yellow solid compound 2b (45.5 mg, 63% yield) was obtained.

[0064] The test data of product 2b are as follows:

[0065] 1 H NMR (400 MHz, CDCl 3 )δ8.20(s,1H),7.67(d,J=10.2Hz,1H),7.15(s,1H),4.87–4.80(m,1H),4.38(q,J=7.2Hz ,2H),3.02(d,J=7.3Hz,2H),2.83–2.72(m,1H),2.51–2.42(m,1H),1.38(t,J=7.2Hz,3H).

[0066] 13 C NMR (101 MHz, CDCl 3 )δ163.5,162.8,137.1,136.8,133.2,129.3,126.4,121.8,114.3(t,J=252.9Hz),72.7,63.6,39.9(t,J=23.6Hz),32.7,14.0.

[0067] 19 F NMR (376 MHz, CDCl 3 )δ-101.34–-102.16(m,1F),-106.82–-107.69(m,1F).

[0068] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 14 H 14 F 2 O 4 ,363.0038;Found:363.0038.

[0069] Example 3

[0070] Prepare isochromanone compound 2c with the following structural formula:

[0071] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allyl-4-fluorobenzoic acid, and the other conditions were the same as in Example 1, and finally a white solid compound 2c (39.8 mg, yield was 66%) was obtained with a melting point of 38.7-40.6°C.

[0072] The test data of product 2c are as follows:

[0073] The melting point is 38.7~40.6℃.

[0074] 1 H NMR (400 MHz, CDCl 3 )δ8.13–8.07(m,1H),7.13–7.06(m,1H),6.99–6.94(m,1H),4.90–4.81(m,1H),4.39(q,J=7 .2Hz,2H),3.11–3.02(m,2H),2.85–2.72(m,1H),2.54–2.42(m,1H),1.38(t,J=7.2Hz,3H).

[0075] 13 C NMR (101 MHz, CDCl 3 )δ167.3,164.7,163.2,141.2(d,J=9.4Hz),133.5(d,J=9.9Hz),121.1(d,J=2.7Hz),116.8, 115.8(d,J=22.1Hz),114.6(t,J=22.3Hz),77.1,72.5,63.6,39.9(t,J=23.9Hz),33.3,14.0.

[0076] 19 F NMR (376 MHz, CDCl 3 )δ-101.81–-102.70(m,1F),-103.09–-103.64(m,1F),-107.31–-108.22(m,1F).

[0077] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 14 H 13 F 3 NaO 4 ,325.0658;Found:325.0653.

[0078] Example 4

[0079] Prepare isochromanone compound 2d with the following structural formula:

[0080] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allyl-5-fluorobenzoic acid, and the other conditions were the same as in Example 1, and finally a yellow oily liquid 2d (41.0 mg, 68% yield) was obtained.

[0081] The product 2d test data is as follows:

[0082] 1 H NMR (400 MHz, CDCl 3 )δ7.74(d,J=9.8Hz,1H),7.25(d,J=6.9Hz,2H),4.88–4.79(m,1H),4.38(q,J=7.2Hz,2 H),3.03(d,J=7.1Hz,2H),2.85–2.70(m,1H),2.53–2.41(m,1H),1.37(t,J=7.2Hz,3H).

[0083] 13 C NMR (101 MHz, CDCl 3 )δ163.3,163.1,160.8,133.9,129.5(d,J=7.4Hz),126.4(d,J=7.3Hz),121.5(d,J=21.9Hz ), 116.8 (d, J = 23.2Hz), 113.0 (t, J = 254.4Hz), 72.9, 63.6, 39.9 (t, J = 23.8Hz), 32.5, 14.0.

[0084] 19 F NMR (376 MHz, CDCl 3 )δ-101.36–-102.19(m,1F),-106.89–-107.84(m,1F),-112.54(s,1F).

[0085] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 14 H 14 F 3 O 4 ,303.0839;Found:303.0839.

[0086] Example 5

[0087] Prepare isochromanone compound 2e with the following structural formula:

[0088]

[0089] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allyl-6-fluorobenzoic acid, and the other conditions were the same as in Example 1, and finally a brown oily liquid compound 2e (39.9 mg, 66% yield) was obtained.

[0090] The test data of product 2e are as follows:

[0091] 1 H NMR (400 MHz, CDCl 3 )δ7.67(d,J=8.1Hz,1H),7.20(d,J=6.8Hz,2H),4.82–4.74(m,1H),4.33(q,J=7.2Hz,2 H),2.98(d,J=7.3Hz,2H),2.78–2.65(m,1H),2.47–2.37(m,1H),1.31(t,J=7.2Hz,3H).

[0092] 13 C NMR (101 MHz, CDCl 3 )δ147.7 146.8,138.0,118.8(d,J=31.0Hz),118.0(d,J=10.3Hz),108.0(t,J=13.2Hz),106.4( d,J=33.0Hz),101.3(t,J=27.6Hz),84.6,77.2,68.4(t,J=23.9Hz),37.7,26.3,19.4.

[0093] 19 F NMR (376 MHz, CDCl 3 )δ-101.31–-102.15(m,1F),-106.84–-107.69(m,1F),-112.36–-112.57(m,1F).

[0094] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C14H14F3O4,303.0839; Found:303.0840.

[0095] Example 6

[0096] Prepare isochromanone compound 2f with the following structural formula:

[0097]

[0098] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allyl-4-chlorobenzoic acid, and the other conditions were the same as in Example 1, and finally a yellow oily liquid compound 2f (35.8 mg, 56% yield) was obtained.

[0099] The test data of product 2f are as follows:

[0100] 1 H NMR (400 MHz, CDCl 3 )δ8.00(d,J=8.2Hz,1H),7.38(d,J=8.4Hz,1H),7.27(s,1H),4.88–4.81(m,1H),4.39(q,J= 7.2Hz,2H),3.09–3.02(m,2H),2.85–2.72(m,1H),2.54–2.42(m,1H),1.38(t,J=7.1Hz,3H).

[0101] 13 C NMR (101 MHz, CDCl 3 )δ163.5,163.3,140.5,139.7,132.0,128.7,127.7,123.1,115.5(t,J=249.0Hz),72.5,63.6,39.9(t,J=23.8Hz),33.0,14.0.

[0102] 19 F NMR (376 MHz, CDCl 3 )δ-102.46–-103.37(m,1F),-107.97–-108.86(m,1F).

[0103] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 14 H 14 CIF 2 O 4 ,319.0543;Found:319.0544.

[0104] Example 7

[0105] Prepare 2g of isochromanone compounds with the following structural formula:

[0106] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allyl-5-chlorobenzoic acid, and the other conditions were the same as in Example 1, and finally 2 g (25.9 mg, 41% yield) of a yellow solid compound was obtained.

[0107] The test data of product 2g are as follows:

[0108] Melting point: 55.5~57.2℃

[0109] 1 H NMR (400 MHz, CDCl 3 )δ8.04(d,J=2.3Hz,1H),7.52(d,J=8.2,2.3Hz,1H),7.22(d,J=8.2Hz,1H),4.87–4.81(m,1H),4.39( q,J=7.2Hz,2H),3.04(d,J=7.3Hz,2H),2.85–2.73(m,1H),2.53–2.44(m,1H),1.38(t,J=7.2Hz,3H).

[0110] 13 C NMR (101 MHz, CDCl 3 )δ163.6(t,J=31.8Hz),162.9,136.4,134.2,130.2,129.1,126.2,115.5(t,J=248.2Hz),77.1,72.7,63.6,39.9(t,J=23.8Hz),32.7,14.0.

[0111] 19 F NMR (376 MHz, CDCl 3 )δ-101.34–-102.16(m,1F),-106.68–-107.89(m,1F).

[0112] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 14 H 14 CIF 2 O 4 ,319.0543;Found:319.0542.

[0113] Example 8

[0114] Prepare isochromanone compound 2h with the following structural formula:

[0115] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced with 2-allyl-5-trifluorobenzoic acid, and the other conditions were the same as in Example 1, and a white oily liquid compound 2h (29.1 mg, 41% yield) was finally obtained. The detection data of the product 2h are as follows:

[0116] 1H NMR (400 MHz, CDCl 3 )δ8.35(s,1H),7.81(d,J=8.1Hz,1H),7.43(d,J=8.0Hz,1H),4.94–4.84(m,1H),4.40(q,J=7. 2Hz,2H),3.15(d,J=7.2Hz,2H),2.89–2.74(m,1H),2.57–2.46(m,1H),1.38(t,J=7.2Hz,3H).

[0117] 13 C NMR (101 MHz, CDCl 3 )δ163.4(q,J=31.0Hz),162.9,141.8,130.9(q,J=33.6Hz),130.5(q,J=3.6Hz),128.5,127. 6(q,J=3.8Hz),125.4,123.4(q,J=272.5Hz),114.2(t),72.6(t),63.9,39.9(t),33.1,14.0.

[0118] 19 F NMR (376 MHz, CDCl 3 )δ-62.95(s,3F),-101.37–-102.19(m,1F),-106.75–-107.62(m,1F).

[0119] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 15 H 14 F 5 O 4 ,353.0807;Found:353.0809.

[0120] Example 9

[0121] Prepare isochromanone compound 2i with the following structural formula:

[0122]

[0123] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allylbenzoic acid, and the other conditions were the same as in Example 1, and finally a white oily liquid compound 2i (31.2 mg, 55% yield) was obtained.

[0124] The test data of product 2i are as follows:

[0125] 1 H NMR (400 MHz, CDCl3 )δ8.06(d,J=7.8Hz,1H),7.55(t,J=7.5Hz,1H),7.41(t,J=7.7Hz,1H),7.27–7.24(m,1H),4.88–4.81(m, 1H),4.42–4.37(m,2H),3.09–3.04(m,2H),2.86–2.72(m,1H),2.53–2.42(m,1H),1.38(t,J=7.2Hz,3H).

[0126] 13 C NMR (101 MHz, CDCl 3 )δ164.1,163.6(t,J=31.4Hz),138.2,134.2,130.5,128.2,127.6,124.7,114.4(t,J=248.2Hz),72.7,63.6,40.0(t,J=22.9Hz),33.2,14.0.

[0127] 19 F NMR (376 MHz, CDCl 3 )δ-101.34–-102.25(m,1F),-106.86–-107.87(m,1F).

[0128] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 14 H 15 F 2 O 4 ,285.0933;Found:285.0936.

[0129] Example 10

[0130] Prepare isochromanone compound 2J with the following structural formula:

[0131]

[0132] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced with 2-allyl-4-methylbenzoic acid, and the other conditions were the same as in Example 1, and finally a yellow oily liquid compound 2J (28.0 mg, 47% yield) was obtained. The test data of the product 2J are as follows:

[0133] 1 H NMR (400 MHz, CDCl 3)δ7.94(d,J=8.0Hz,1H),7.20(d,J=8.0Hz,1H),7.05(s,1H),4.88–4.76(m,1H),4.39(q,J=7.2Hz, 2H),3.06–2.95(m,2H),2.83–2.69(m,1H),2.52–2.42(m,1H),2.40(s,3H),1.37(t,J=7.2Hz,3H).

[0134] 13 C NMR (101 MHz, CDCl 3 )δ164.2,163.6(t,J=31.4Hz),145.2,138.1,130.4,129.0,128.1,122.0 ,114.4(t,J=258.1Hz),72.5,63.5,40.0(t,J=23.7Hz),33.2,21.8,14.0.

[0135] 19 F NMR (376 MHz, CDCl 3 )δ-101.34–-102.18(m,1F),-106.83–-107.77(m,1F).

[0136] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 15 H 17 F 2 O 4 ,299.1089;Found:299.1084.

[0137] Embodiment 11

[0138] Prepare isochromanone compound 2k with the following structural formula:

[0139]

[0140] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced with 2-allyl-4-methoxybenzoic acid, and the other conditions were the same as in Example 1, and finally a yellow oily liquid compound 2k (46.2 mg, 74% yield) was obtained. The detection data of the product 2k are as follows:

[0141] 1 H NMR (400 MHz, CDCl 3)δ8.00(d,J=8.6Hz,1H),6.89(d,J=6.2Hz,1H),6.71(d,J=2.5Hz,1H),4.85–4.77(m,1H),4.39(q,J=7. 2Hz,2H),3.86(s,3H),3.07–2.97(m,2H),2.84–2.70(m,1H),2.52–2.40(m,1H),1.37(t,J=7.1Hz,3H).

[0142] 13 C NMR (101 MHz, CDCl 3 )δ164.3(t,J=5.9Hz),140.5,132.8,132.5,117.1,114.0,113.4(t,J=28.7Hz),112.3,72.3,63.6,55.7,39.9(t,J=23.6Hz),33.5,14.0.

[0143] 19 F NMR (376 MHz, CDCl 3 )δ-102.41–-103.65(m,1F),-108.00–-108.94(m,1F).

[0144] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 15 H 17 F 2 O 5 ,315.1039;Found:315.1039.

[0145] Example 12

[0146] Prepare isochromanone compound 21 with the following structural formula:

[0147]

[0148] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced with 2-allyl-4,5-dimethoxybenzoic acid, and the other conditions were the same as in Example 1, and finally a yellow oily liquid compound 21 (47.6 mg, 69% yield) was obtained. The detection data of the product 2i are as follows:

[0149] 1 H NMR (400 MHz, CDCl 3)δ7.48(s,1H),6.66(s,1H),4.85–4.76(m,1H),4.37(q,J=7.1Hz,2H),3.90(d,J=13.3H z,6H),3.02–2.92(m,2H),2.81–2.69(m,1H),2.51–2.39(m,1H),1.36(t,J=7.1Hz,3H).

[0150] 13 C NMR (101 MHz, CDCl 3 )δ164.2,163.6(t,J=31.9Hz),154.0,148.8,131.8,116.8,115.6(t,J=251.4Hz),111.7,109 .4,72.6(t,J=6.7Hz),63.5,56.3,56.2,39.9(t,J=23.6Hz),32.9,30.0(t,J=16.8Hz),14.0.

[0151] 19 F NMR (376 MHz, CDCl 3 )δ-100.66–-101.51(m,1F),-106.77–-107.72(m,1F).

[0152] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 16 H 19 F 2 O 6 ,345.1144;Found:345.1146.

[0153] Example 13

[0154] Prepare isochromanone compound 2m with the following structural formula:

[0155]

[0156] The 2-allyl-4-bromobenzoic acid in Example 1 was replaced by 2-allyl-4-methoxybenzoic acid, and the difluoroethyl iodoacetate was replaced by 1-iodoperfluorohexane. Other conditions were the same as in Example 1, and finally a yellow oily liquid compound 2m (69.2 mg, 68%) was obtained.

[0157] The product 2m test data is as follows:

[0158] 1 H NMR (400 MHz, CDCl 3)δ8.03(d,J=8.7Hz,1H),6.91(d,J=8.7Hz,1H),6.72(s,1H),4.99–4.90(m, 1H),3.87(s,3H),3.13–3.02(m,2H),2.86–2.71(m,1H),2.58–2.42(m,1H).

[0159] 13 C NMR (101 MHz, CDCl 3 )δ164.3(d,J=5.3Hz),140.3,132.9,119.8(t,J=32.0Hz),118.8–117.3(m),117.2,117.0–114.7(m),114.2,114.0– 112.6(m),112.4,111.1(t,J=32.8Hz),108.4(t,J=33.2Hz),77.5,77.2,76.8,71.5,55.7,36.3(t,J=21.1Hz),34.2.

[0160] 19 F NMR (376 MHz, CDCl 3 )δ-80.85(t,3F),-111.25–-112.07(m,1F),-112.92–-113.74(m,1F),-121.83(s,2F),-122.91(s,2F),-123.54(s,2F),-126.19(s,2F).

[0161] HRMS (ESI, Q-TOF) m / z: [M+Na + ]Calcd for C 17 H 11 F 13 NaO 3 ,533.0393;Found:533.0391.

[0162] Embodiment 14

[0163] Fluoroalkyl-substituted isochromanone compound 2b was derived to give compound 3:

[0164]

[0165] Fluoroalkyl-substituted isochromanone compound 2b (0.2mmol), palladium acetate (0.01mmol), phenylboronic acid (0.3mmol), n-butyl di(1-adamantyl) phosphine (0.02mmol), and cesium carbonate (0.4mmol) were added to DCE (1,2-dichloroethane, 2mL) in sequence. After the reaction bottle was evacuated with an oil pump, argon gas was injected into the bottle (repeated three times), and it was placed in an 80°C oil bath and stirred for reaction. After 12 hours, the reaction was cooled to room temperature. The reaction solution was extracted, dried, filtered, concentrated, and chromatographed on a silica gel column to obtain a light yellow solid compound 3 (43.3mg, 60% yield).

[0166] The test data of product 3 are as follows:

[0167] Melting point: 95.1-96.9℃

[0168] 1 H NMR (400 MHz, CDCl 3 )δ8.13(d,J=7.9Hz,1H),7.65–7.57(m,3H),7.51–7.39(m,4H),4.95–4.84(m,1H),4.41(q,J=7 .0Hz,2H),3.12(d,J=5.4Hz,2H),2.90–2.74(m,1H),2.57–2.43(m,1H),1.39(t,J=7.2Hz,3H).

[0169] 13 C NMR (101 MHz, CDCl 3 )δ163.8(t,J=48.4Hz),147.0,139.5,138.7,131.1,129.2,128.7,127.4,126.9,126.2 ,123.4,114.5(t,J=250.3Hz),72.7(t,J=6.9Hz),63.6,40.1(t,J=23.7Hz),33.5,14.0.

[0170] 19 F NMR (376 MHz, CDCl 3 )δ-101.21--102.08(m,1F),-106.66--107.64(m,1F).

[0171] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 20 H 19 F 2 O 4,361.1246;Found:361.1243.

[0172] Anti-tumor activity verification

[0173] The difluoroalkyl-substituted isochromanone compounds prepared in the examples were selected and their in vitro antitumor activity (MTS method) was tested using human myeloid leukemia cell line (HL-60) as a receptor.

[0174] Experimental methods:

[0175] (1) Inoculation of cells: Use culture medium (RMPI1640) containing 10% fetal bovine serum to prepare a single cell suspension, and inoculate 15,000 cells per well into a 96-well plate, with a volume of 100 μl per well. The cells are inoculated and cultured 12 to 24 hours in advance. (2) Add the solution of the compound to be tested: The compound is dissolved in DMSO, and the specific screening concentrations (μM) of the compound are 0.16, 0.8, 4, 20, and 100, respectively. The final volume of each well is 200 μl, and 3 replicate wells are set for each treatment. (3) Color development: After culturing at 37 degrees Celsius for 48 hours, discard 100 μl of the culture supernatant of the suspended cells, and add 20 μl of MTS solution to each well; discard 100 μl of the culture supernatant of the suspended cells, and add 20 μl of MTS solution to each well; set up 3 blank replicate wells (a mixture of 20 μl MTS solution and 100 μl culture medium), and continue incubation for 2 to 4 hours to allow the reaction to proceed fully before measuring the light absorption value. (4) Colorimetry: Select 492nm wavelength, read the light absorption value of each well with a multifunctional microplate reader (MULTISKAN FC), record the results, and after data processing, draw a cell growth curve with concentration as the horizontal axis and cell survival rate as the vertical axis. Calculate the IC50 value of the compound using the two-point method (Reed and Muench method). (5) Positive control compound: In all experiments, cisplatin (DDP) was set as the positive compound, and the cell growth curve was drawn with concentration as the horizontal axis and cell survival rate as the vertical axis. Calculate the IC50 value of the compound using the two-point method (Reed and Muench method).

[0176] Table 1 shows the inhibitory effects of some compounds in the examples on the proliferation of human myeloid leukemia cell line (HL-60).

[0177]

[0178]

[0179] It can be seen that the fluorine-containing isochromanone compounds provided by the present invention have certain activity in inhibiting the proliferation of leukemia cells.

[0180] The above is only an embodiment of the present invention, and the common knowledge such as the known specific structure and characteristics in the scheme is not described in detail here. It should be pointed out that for those skilled in the art, several deformations and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A fluoroalkyl-substituted isochromanone compound, characterized in that: Its structural formula is as follows: wherein R is independently selected from hydrogen, 8-fluoro, 8-chloro, 8-bromo, 8-iodo, 7-fluoro, 7-chloro, 7-bromo, 7-iodo, 7-trifluoromethyl, 7-methoxy, 7-methyl, 6-fluoro, 6-chloro, 6-bromo, 6-iodo, 6-trifluoromethyl, 6-methoxy, 6-methyl, 5-fluoro, 5-chloro, 5-bromo, 5-iodo, 5-methyl, 5-trifluoromethyl, 5-methoxy, 6, 7-dimethoxy, 6, 7-dimethyl, 6 -fluoro-7-methoxy, 6-bromo-7-methoxy, 6-chloro-7-methoxy, 6-iodo-7-methoxy, 6-methoxy-7-iodine, 6-methoxy-7-bromo, 6-methoxy-7-chloro, 6-methoxy-7-fluoro, 7-bromo-8-fluoro, 6-bromo-7-fluoro, 6,7-difluoro, 6,7-dichloro, 5-methoxy-8-fluoro, 5-methoxy-8-chloro, 5-methyl-8-fluoro or 5-methyl-8-chloro; R' is selected from ethoxycarbonyl, methoxycarbonyl, perfluoro-n-butyl, perfluoro-n-propyl, perfluoro-isopropyl, perfluoro-n-pentyl, perfluoro-n-hexyl, perfluoro-n-heptyl or perfluoro-n-octyl.

2. The method for preparing isochromanone compounds according to claim 1, characterized in that: Mixing 2-allylarylcarboxylic acid, difluoro or perfluoro iodoalkane, silver salt and an organic solvent, heating reaction and subsequent separation and purification to obtain a fluoroalkyl substituted isochromanone compound; 3. The preparation method according to claim 2, characterized in that: The silver salt is selected from silver acetate, silver oxide, silver carbonate, silver trifluoroacetate or silver chloride.

4. The preparation method according to claim 3, characterized in that: The organic solvent is selected from acetonitrile, tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or ethyl acetate.

5. The preparation method according to claim 3 or 4, characterized in that: The temperature is 20°C to 100°C; the time is 2h to 40; and the gas atmosphere is selected from air, nitrogen or argon.

6. The preparation method according to claim 5, characterized in that: The molar ratio of 2-allyl aromatic carboxylic acid: difluoro or perfluoro iodoalkane: silver salt is 1:1-5:0.1-2.

7. The preparation method according to claim 6, characterized in that: The separation and purification method is selected from silica gel column chromatography and recrystallization.

8. Use of the isochromanone compounds according to claim 1 in the preparation of anti-leukemia drugs.

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